The majority of autoimmune diseases are chronic conditions, characterized by persistent or relapsing inflammation in the target organ. This is certainly true of multiple sclerosis (MS), an inflammatory disease of central nervous system (CNS) white matter, which generally presents with recurrent episodes of neurological dysfunction followed by a secondary stage of gradually worsening disability. Experimental autoimmune encephalomyelitis (EAE), an animal model with strong pathological similarities to MS, also follows a relapsing, progressive clinical course (Raine, C. S., et al. 1984. Laboratory Investigation 51:534-546).
In the human disease multiple sclerosis (MS) and the animal model, experimental autoimmune encephalomyelitis (EAE), chronic or relapsing inflammation in the central nervous system (CNS) results in destruction of the myelin sheath. EAE is induced in naïve mice by the adoptive transfer of CD4+ T-cells specific for myelin proteins (Raine, C. S., et al. 1984. Laboratory Investigation 51:534-546). Once these effector cells cross the blood-brain-barrier, they activate resident microglia and recruit peripheral leukocytes to the CNS (Bauer, J., et al. 1995. Glia 15:437). Perivascular infiltrates are subsequently formed within the white matter and evolve into lymphoid-myeloid aggregates over time.
In acute lesions, myeloid cells dominate the inflammatory infiltrate (Bauer, J., et al. 1995. Glia 15:437). T-cells become more numerous in chronic lesions and are sometimes found in association with dendritic-like (dendriform) cells. B cells and plasma cells are also frequently present, and tend to localize in regions distinct from those containing T-cells (Raine, C. S., et al. 1984. Laboratory Investigation 51:534-546, Paterson, P. Y., and Swanborg, R. H. 1988. In: Immunological Diseases (ed. Samter, M.), Traugott, U., et al. 1983. Journal of Neuroimmunology 4:201-221). Even lymphatic capillaries have been demonstrated in the CNS tissues of patients with long standing MS (Prineas, J. W., and Wright, R. G. 1978. Laboratory Investigation 38:409-421). The structured appearance and cellular composition of these chronic CNS lesions are reminiscent of secondary lymphoid tissues. Similarly, in EAE white matter infiltrates exhibit features normally associated with lymph nodes and spleen including perivascular T-cell cuffs (approximating periarterial sheaths in the spleen), lymphoid-myeloid aggregates, and blood vessels with characteristics of high endothelial venules (HEV).
Several features of chronic inflammatory infiltrates in autoimmune lesions parallel the architectural characteristics of secondary lymphoid tissues. For example, T and B cells tend to segregate into distinct areas of chronic MS plaques, similar to the T-cell- and B cell-rich areas of lymph node and spleen (Raine, C. S., et al. 1984. Laboratory Investigation 51:534-546, Paterson, P. Y., and Swanborg, R. H. 1988. In: Immunological Diseases (ed. Samter, M.)-3). Lymphatic-like capillaries have been identified in long-standing MS lesions (Prineas, J. W., and Wright, R. G. 1978. Laboratory Investigation 38:409-421). Furthermore, myeloid dendritic cells, a critical class of antigen presenting cells (APC) that serve to activate T-cells in peripheral lymphoid organs, have recently been detected in MS and EAE lesions (Ulvestad, E., et al. 1994. J Leukoc Biol. 56:732-40, Fischer, H. G. and Reichmann, G. 2001. J. Immunol. 166:2717, (Serafini, B., et al. 2000. American Journal of Pathology 157:1991-2002). Interestingly, microglia acquire dendritic-like cell characteristics following stimulation with GM-CSF in vitro, raising the possibility that dendritic cells differentiate from CNS glial cells in vivo (Fischer, H. G. and Reichmann, G. 2001. J. Immunol. 166:2717, Santambrogio, L., et al. 2001. PNAS 98:6295, Aloisi, F., et al. 2000. J. Immunol. 164:1705). Although these studies suggest that autoimmune infiltrates evolve using similar pathways to those that guide the development and organization of secondary lymphoid tissues, needed in the art are specific agents that modulate relevant pathways involved in autoimmune disease.
CXCL13, also known as B-lymphocyte chemoattractant (BLC), B-cell-attracting chemokine 1 (BCA1), and Angie-2, is a protein of about 88 amino acids in the group of CXC-Chemokines. The receptor for CXCL13 is CXCR5 (also known as BLR-1 and MDR15), although CXCR3 has also been identified as a receptor.